Sickle cell disease (SCD) is a genetic blood disorder characterized by red blood cells (RBCs) that assume an abnormal rigid sickle shape. Sickling decreases the RBCs flexibility and results in a risk of various complications (Serjent G R. Sickle cell disease, 3rd edition, New York: Oxford University Press; 2001, Homozygous sickle cell disease; pp. 429-35). Sickle cell disease is the most prevalent human hereditary disorder with prominent morbidity and mortality. Sickle cell disease is due to the change of an amino acid in position six within the beta globin chain of hemoglobin molecule, whereby glutamic acid, a polar amino acid is replaced by valine, a non-polar amino acid (Pauling L, Itano, H A., Sickle cell anemia a molecular disease, Science. 1949; 110:543-8); (Ingram V M., Gene mutations in human hemoglobin: The chemical difference between normal and sickle cell hemoglobin, Nature, 1957; 180:326-8). The amino acid change is due to the defective gene (mutation) in chromosome 11. At low oxygen tension, the mutant hemoglobin polymerizes inside the RBCs into a gel or further into fibers leading to a drastic decrease in the red cell deformability. Polymerization and precipitation of sickle hemoglobin (HbS) within the erythrocytes cause the change of shape from the normal spherical form into the one resembling a sickle, hence the name sickle cell.
The SCD has been reported to be wide spread in Africa, Jamaica, Central India, Saudi Arabia, Greece and Italy and also among Africans in America and Britain. SCD affects millions of people throughout the world (Report by the Secretariat; 117th session of Executive Board (EB117/34) Geneva: World Health Organization; 2005, WHO, Sickle cell anemia; p. 1). Clinical symptoms of patients suffering from the disease vary widely some suffer from a variety of life threatening complications. The main clinical symptoms are anemia; mild jaundice, repeated vasooclusive crises, hepatosplenomegaly, acute chest syndrome; bone, joint pain, growth retardation, and other secondary complications (Serjent G R. Sickle cell disease, 3rd edition, New York: Oxford University Press; 2001, Homozygous sickle cell disease; pp. 429-35).
The health-care cost of the management of SCD patients is disproportionately high compared to the number of people afflicted by the disease.
The fundamental cause of SCD is the decreased deformability of the sickled RBCs produced by gelation of hemoglobin S molecules during de-oxygenation. The deformation of sickle red cells upon complete de-oxygenation is due to the intracellular HbS polymerization. The gelation or polymerization is initiated by nucleation of a single polymer. Two types of HbS nucleation (i.e., homogeneous and heterogeneous) have been observed. The nucleation is due to the aggregation of hemoglobin S molecules. Once a certain size or the critical nucleus is reached, other monomers of HbS add endlessly to form a very large polymer. Then due the heterogeneous nucleation polymers are formed on the surface of the pre-existing polymer. Individual polymer is a fiber which is made up of 14 inter-wined helical strands of HbS molecules of seven inter-wined double strands. In each molecule, one of the two β6 Valines of the α2 β2 tetramer is involved in an intermolecular contact with its neighbor in the double strand (Report by the Secretariat, 117th session of Executive Board (EB117/34) Geneva: World Health Organization; 2005, WHO, Sickle cell anemia; p. 1).
Oxidative stress may contribute to the sickling process with formation of dense cells, development of vasoocciusion and shortened RBC survival. Oxidative damage in sickle RBC is most likely the consequence of the inherent instability of hemoglobin S, which results in a concomitant increase in free radical generation in association with impaired antioxidant defense (Lachant N A, Tanaka K R., Antioxidants in sickle cell disease: The in vitro effects of ascorbic acid, Am J Med Sci. 1986; 292:3-10).
Peripheral blood smears of subjects with steady sickle cell disease (SCD) with controls by counting ten 100× microscope fields were used to calculate percent of irreversible and reversible SC from total red cell population SC index (SCI). Controls had a small SCI. Children with hemoglobin SS had a significantly higher SCI. SCI increased with each increasing year and patients with higher SCI are likely to experience clinical complications (Alvarez O, Montague N S, Marin M, O'Brien R, Rodriguez M M, Quantification of Sickle Cells in the Peripheral Smear as a Marker of Disease Severity, Fetal Pediatr Pathol. 2015 June; 34(3):149-54). Although blood transfusions and hydroxyurea slightly decreased SCI, 72% treated patients still had high SCI, correlating with persistent sickling (Alvarez O, Montague N S, Mann M, O'Brien R, Rodriguez M M, Quantification of Sickle Cells in the Peripheral Smear as a Marker of Disease Severity, Fetal Pediatr Pathol. 2015 June; 34(3):149-54). In conclusion, transfusion and/or hydroxyurea have little impact on SCI, highlighting a need for a more effective anti-sickling strategy.